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Nat Commun. 2015 Dec 22;6:10111. doi: 10.1038/ncomms10111.

Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.

Author information

  • 1Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
  • 2The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210023, China.
  • 3Interdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research &Technology (SMART), Singapore 138602, Singapore.
  • 4Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
  • 5Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore.
  • 6Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore.
  • 7NUS Environmental Research Institute, Singapore 117411, Singapore.
  • 8Department of Anaesthesiology, Singapore General Hospital, Singapore 169608, Singapore.
  • 9School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
  • 10College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
  • 11Department of Biomedical Engineering, National University of Singapore, Singapore 117583, Singapore.
  • 12Department of Mechanical Engineering, National University of Singapore, Singapore 117575, Singapore.

Abstract

The mechanism of action of artemisinin and its derivatives, the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chemical proteomics analysis to directly explore this mechanism in Plasmodium falciparum. We use an alkyne-tagged artemisinin analogue coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biological processes of the parasite. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from haemoglobin digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing.

PMID:
26694030
[PubMed - indexed for MEDLINE]
PMCID:
PMC4703832
Free PMC Article
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